Human papillomaviruses (HPVs) are strongly implicated in the development of cervical carcinoma and other anogenital cancers. Treatment of precancerous lesions is not effective in all patients. Spontaneous regression is common but not universal, and may not occur for years. Immune activity to a number of HPV proteins has been reported. Therefore vaccination to HPV holds promise for preventing precancerous lesions from developing or inducing or accelerating their regression. Vaccine development cannot rely initially on clinical experimentation because of the difficulties in identifying HPV-negative subjects because of the plethora of HPV types, and because recurrence of precancerous lesions and HPV reinfection are common. In addition, it has been impossible to induce disease in animals with HPVs. The best animal model for HPV disease that progresses to cancer is cottontail rabbit papillomavirus (CRPV) infection of laboratory rabbits. We propose to utilize the CRPV model to develop PV vaccines. Initial experiments will identify CRPV genes coding for proteins that elicit immunity which protects against papilloma formation or induces papilloma regression. Subsequent experiments will evaluate the ability of corresponding HPV genes, expressed in recombinant CRPV viruses, to elicit protective or therapeutic immunity. Once effective PV vaccines are identified, their value as possible direct anti-cancer vaccines can be tested using, for example, transplantable rabbit carcinomas induced by CRPV or CRPV/HPV recombinants as model targets.